Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV004562096 | SCV001416958 | pathogenic | Familial adenomatous polyposis 1 | 2024-05-13 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Thr1633Cysfs*5) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1211 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002339675 | SCV002634791 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-04-19 | criteria provided, single submitter | clinical testing | The c.4897delAinsTG pathogenic mutation, located in coding exon 15 of the APC gene, results from the deletion of one nucleotide and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon (p.T1633Cfs*5). This alteration occurs at the 3' terminus of the APC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last exon of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). As such, this alteration is interpreted as a disease-causing mutation. |